Radiographic techniques such as scintigraphy, and the like, find application in biological and medical procedures for diagnosis as well as research. Scintigraphy involves the use of radiopharmaceuticals; i.e., compounds containing (or labeled with) a radioisotope (i.e. radionuclide) which upon introduction into a mammal become localized in specific organs, tissue, or skeletal material that are sought to be imaged. When the radiopharmaceutical is so localized, traces, plates, or scintiphotos of the existing distribution of the radionuclide may be made by various radiation detectors known in the art. The observed distribution of the localized radionuclide can then be used to detect the presence of pathological conditions, abnormalities, and the like. Radiopharmaceuticals are thus often referred to as radiodiagnostics.
In many cases, radiopharmaceuticals are prepared using target-specific chelating agents which provide a bridge connecting a radionuclide, such as a radioactive metal like technetium-99m, or the like, and a material which will temporarily localize in the organ, tissue, or skeletal material which is to be imaged. Typical chelating agents for such purposes are: polydentate ligands that form a 1:1 or 2:1 ligands:radioactive metal complex; macrocyclic ligands of appropriate ring size and preferably where all coordinating atoms are in a planar configuration; and bicyclic or polycyclic ligands that can encapsulate the radioactive metal.
It is a well established fact that the delivery of drugs, including radiopharmaceuticals, to the brain is often seriously limited by transport and metabolism factors and, more specifically, by the functional barrier of the endothelial brain capillary wall deemed the blood-brain barrier of BBB. Site-specific delivery and/or sustained delivery of drugs to the brain are even more difficult.
A dihydropyridine.revreaction.pyridinium redox system has now been successfully applied to delivery to the brain of a number of drugs. Generally speaking, according to this system, a dihydropyridine derivative of a biologically active compound is synthesized, which derivative can enter the CNS through the blood-brain barrier following its systemic administration. Subsequent oxidation of the dihydropyridine species to the corresponding pyridinium salt leads to delivery of the drug to the brain.
Two main approaches have been used thus far for delivering drugs to the brain using this redox system. The first approach involves derivation of selected drugs which contain a pyridinium nucleus as an integral structural component. This approach was first applied to delivering to the brain N-methylpyridinium-2-carbaldoxime chloride (2-PAM), the active nucleus of which consitutes a quaternary pyridinium salt, by way of the dihydropyridine latentiated prodrug form thereof. Thus, a hydrophilic compound (2-PAM) was made lipoidal (i.e. lipophilic) by making its dihydropyridine form (Pro-2-PAM) to enable its penetration through lipoidal barriers. This simple prodrug approach allowed the compound to get into the brain as well as other organs, but this manipulation did not and could not result in any brain specificity. On the contrary, such approach was delimited to relatively small molecule quaternary pyridinium ring-containing drug species and did not provide the overall ideal result of brain-specific, sustained release of the desired toxicity. No "trapping" in the brain of the 2-PAM formed in situ resulted, and obviously no brain-specific, sustained delivery occurred as any consequence thereof: the 2-PAM was eliminated as fast from the brain as it was from the general circulation and other organs. Compare U.S. Pat. Nos. 3,929,813 and 3,962,447; Bodor et al., J. Pharm. Sci., 67, No. 5, pp. 685-687 (1978); Bodor et al, Science, Vol. 190 (1975), pp. 155-156; Shek, Higuchi and Bodor, J. Med. Chem., Vol. 19 (1976), pp. 113-117. A more recent extension of this approach is described by Brewster, Dissertation Abstracts International, Vol. 43, No. 09, Mar. 1983, p. 2910B. See also Bodor et al, Science, Vol. 214, Dec. 18, 1981, pp. 1370-1372.
The second approach for delivering drugs to the brain using the redox system involves the use of a pyridinium carrier chemically linked to a biologically active compound. Bodor et al, Science, vol. 213, Dec. 18, 1981, pp. 1370-1372, outlines a scheme for this specific and sustained delivery of drug species to the brain, as depicted in the following Scheme A: ##STR1## According to the scheme in Science, a drug [D] is coupled to a quaternary carrier [QC].sup.+ and the [D-QC].sup.+ which results is then reduced chemically t the lipoidal dihydro form [D-DHC]. After administration of [D-DHC] in vivo, it is rapidly distributed throughout the body, including the brain. The dihydro form [D-DHC] is then in situ oxidized (rate constant, k.sub.1) (by the NAD.revreaction.NADH system) to the ideally inactive original [D-QC].sup.+ quaternary salt which, because of its ionic, hydrophilic character, should be rapidly eliminated from the general circulation of the body, while the blood-brain barrier should prevent its elimination from the brain (k.sub.3 &gt;&gt;k.sub.2 ; k.sub.3 &gt;&gt;k.sub.7). Enzymatic cleavage of the [D-QC].sup.+ that is "locked" in the brain effects a sustained delivery of the drug species [D], followed by its normal elimination (k.sub.5), metabolism. A properly selected carrier [QC].sup.+ will also be rapidly eliminated from the brain (d.sub. 6 &gt;&gt;k.sub.2). Because of the facile elimination of [D-QC].sup.+ from the general circulation, only minor amounts of drug are released in the body (k.sub.3 &gt;&gt;k.sub.4); [D] will be released primarily in the brain (k.sub.4 &gt;K.sub.2). The overall result ideally will be a brain-specific sustained release of the target drug species. Specifically, Bodor et al worked with phenylethylamine as the drug model. That compound was coupled to nicotinic acid, then quaternized to give compounds of the formula ##STR2## which were subsequently reduced by sodium dithionite to the corresponding compounds of the formula ##STR3## Testing of the N-methyl derivative in vivo supported the criteria set forth in Scheme A. Bodor et al speculated that various types of drugs might possibly be delivered using the depicted or analogous carrier systems and indicated that use of N-methylnicotinic acid esters and amides and their pyridine ring-substituted derivatives was being studied for delivery of amino- or hydroxyl-containing drugs, including small peptides, to the brain. No other possible specific carriers were disclosed. Other reports of this work with the redox carrier system have appeared in The Friday Evening Post, Aug. 14, 1981, Health Center Communications, University of Florida, Gainesville, Fla.; Chemical & Engineering News, Dec. 21, 1981, pp. 24-25; and Science News, Jan. 2, 1982, Vol. 121, No. 1, page 7. More recently, the present inventor has substantially extended the redox carrier system in terms of possible carriers and drugs to be delivered; see, for example International Patent Application No. PCT/US83/00725, filed by University of Florida on May 12, 1983 and published under International Publication No. WO83/03968 on Nov. 24, 1983.
Nevertheless, serious need also has existed in this art for new, centrally acting drugs which can be site-specifically and sustainedly delivered to the brain, while at the same time avoiding the afforesaid noted and notable disadvantages and drawbacks associated with penetration of the blood-brain barrier, with dihydropyridine lateniated prodrug forms of drug species themselves comprising a pyridinium salt active nucleus, with the necessity for introducing critically coordinated and designed, release rate-controlling substituents onto any particular drug carrier moiety, and/or with the limitation of delivery of only known drug entities. This need has led to a new approach for delivering drugs to the brain using the redox system. This novel approach provides new derivatives of centrally acting amines in which a primary, secondary or tertiary amino function has been replaced with a dihydropyridine/pyridinum salt redox system. These new dihydropyridine analogues are characterized by the structural formula ##STR4## wherein D is the residue of a centrally acting primary, secondary or tertiary amine, and ##STR5## is a radical of the formula ##STR6## wherein the dotted line in formula (i) indicates the presence of a double bond in either the 4 or 5 position of the dihydropyridine ring; the dotted line in formula (ii) indicates the presence of a double bond in either the 2 or 3 position of the dihydroquinoline ring system; m is zero or one; n is zero, one or two; p is zero, one or two, provided that when p is one or two, each R in formula (ii) can be located on either of the two fused rings; q is zero, one, or two, provided that when q is one or two, each R in formula (iii) can be located on either of the two fused rings; and each R is independently selected from the group consisting of halo, C.sub.1 -C.sub.7 alkyl, C.sub.1 -C.sub.7 alkoxy, C.sub.2 -C.sub.8 alkoxycarbonyl, C.sub.2 -C.sub.8 alkanoyloxy, C.sub.1 -C.sub.7 haloalkyl, C.sub.1 -C.sub.7 alkylthio, C.sub.1 -C.sub.7 alkylsulfinyl, C.sub.1 -C.sub.7 alkylsulfonyl, CH.dbd.NOR'" wherein R'" is H or C.sub.1 -C.sub.7 alkyl, and --CONR'R" wherein R' and R", which can be the same or different, are each H or C.sub.1 -C.sub.7 alkyl.
The new dihydropyridine analogues described in the preceding paragraph act as a delivery system for the corresponding quaternary compounds in vivo; the quaternary derivatives, which also are chemical intermediates to the dihydro compounds, are pharmacologically active and are characterized by site-specific and sustained delivery to the brain when administered via the corresponding dihydropyridine form. Nevertheless, a serious need still exists for an effective general method for the site-specific and/or sustained delivery of a desired radionuclide to the brain. It would therefore be desirable to adapt the analogue concept to the radiopharmaceutical area.